Abstract Immunotherapies such as checkpoint inhibitors have demonstrated exciting clinical responses in the recent years, demonstrating the important role of host immune system in cancer. We were the first group to report a novel population of immunosuppressive monocytes, characterized by a loss of HLA-DR expression (CD14+HLA-DRlow/neg), in lymphoma, renal cell carcinoma, glioblastoma multiforme and other cancer types. These cells are PD-1 positive in lymphoma tumors. We have characterized the suppressive functions of these cells on systemic immunity and demonstrated correlation of these cells to decreased PFS and OS. Other researchers have reported corroborative findings in other cancer types. While many in the field have termed these cells as monocytic myeloid derived suppressor cells (MDSC) based on their immune functions, we have also identified immune independent mechanism by which these cells directly promote chemo-resistance in lymphoma. Therefore we believe that these cells have a broader spectrum of functions than MDSC and have defined them as regulatory monocytes, Mreg. Our central hypothesis is that lymphoma tumor and Mreg croos talk is a key mechanism that leads to suppression of anti-lymphoma immunity and chemotherapy resistance, thereby, reducing survival. In this R01 proposal, we will examine Mreg lymphoma crosstalk that promotes treatment resistance and identify potential therapeutic strategies. This will be achieved through three specific aims: 1) Identify the mechanisms of Mreg mediated lymphoma resistance to chemotherapy, specifically focusing on Hsp27 signaling. Animal model will be developed to examine Mreg lymphoma interaction in chemo-resistance, including primary patient tumor xenografts and testing of Apatorsen, an anti-sense oligonucleotide that inhibits Hsp27 in clinical trial development for solid tumors. 2) Examine strategies to reprogram Mreg to improve anti-lymphoma immunity, specifically testing blockade of Hsp27 and PD-1/PD-L1/L2 in lymphoma Mreg crosstalk and stimulation with toll-like receptor-7 (TLR7) agonist. In addition we will examine a novel liposome-packaged drug delivery system to target Mreg. 3) Identify the prognostic significance of intra-tumor Mreg. Completion of Aims 1 and 2 will identify more than one potential treatment strategies targeting Mreg lymphoma crosstalk for clinical trial development. Completion of Aim 3 will assist the development of a personalized therapy approach where patients with high levels intra-tumor Mreg will receive therapy targeting Mreg lymphoma crosstalk.